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Objective: This study aims to identify causal variants associated with vitiligo in an expanded region of 10q22.1. Materials and Methods: We conducted a fine-scale deep analysis of the expanded 10q22.1 region using in a large genome-wide association studies dataset consisting of 1117 cases and 1701 controls through imputation. We selected five nominal coding single nucleotide polymorphisms (SNPs) located in SLC29A3 and CDH23 and genotyped them in an independent cohort of 2479 cases and 2451 controls in a Chinese Han population cohort using the Sequenom MassArray iPLEX1 system. Results: A missense SNP in SLC29A3, rs2252996, showed strong evidence of association with vitiligo (p = 1.34 × 10-8, odds ratio [OR] = 0.82). Three synonymous SNPs (rs1084004 in SLC29A3; rs12218559 and rs10999978 in CDH23) provided suggestive evidence of association for vitiligo (p = 1.69 × 10-6, OR = 0.84; p = 9.47 × 10-5, OR = 1.18; p = 6.90 × 10-4, OR = 1.16, respectively). Stepwise conditional analyses identified two significant independent disease-associated signals from the four SNPs (both p < 0.05; both D' = 0.03; and r2 = 0.00). Conclusion: The study identifies four genetic coding variants in SLC29A3 and CDH23 on 10q22.1 that may contribute to vitiligo susceptibility with one missense variant affecting disease subphenotypes. The presence of multiple genetic variants underscores their significant role in the genetic pathogenesis of the disease.
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Proteínas Relacionadas a Caderinas , Proteínas de Transporte de Nucleosídeos , Vitiligo , Humanos , China , Estudo de Associação Genômica Ampla , Genótipo , Proteínas de Transporte de Nucleosídeos/genética , Vitiligo/genética , População do Leste Asiático , Proteínas Relacionadas a Caderinas/genéticaRESUMO
Objective: To explore the effects of a micro-video-based flipped classroom teaching model on the standardized training of dermatological residents in China. Methods: A total of 78 residents who had received standardized training at the Department of Dermatology of the First Affiliated Hospital of Anhui Medical University were selected and randomly divided into an experimental group (39 residents) and a control group (39 residents). The experimental group received micro-video-based flipped classroom teaching, whereas the control group received traditional lecture-based classroom teaching. Scores relating to theoretical knowledge of dermatology, clinical practice skills, and the results of a questionnaire survey were used to evaluate the teaching effects. Results: The average score of the experimental group in the theoretical knowledge test (88.56 ± 5.80) was significantly higher than that of the control group (81.90 ± 7.45). Similarly, the average score of the experimental group in the clinical practice skills test (85.44 ± 5.97) was also significantly higher than that of the control group (78.46 ± 5.94). The results of the questionnaire survey showed that the experimental group exhibited significant improvements in learning interest, mastery of teaching content, communication skills, expression skills, clinical practice skills, autonomous learning, clinical thinking, clinical application, and team cooperation. Conclusion: Flipped classroom teaching based on micro-videos helped to improve the teaching effects of theoretical knowledge, clinical practice skills, and residents' comprehensive ability during dermatological residents' standardized training.
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BACKGROUND: Psoriasis is a chronic and hyperproliferative skin disease featured by hyperkeratosis with parakeratosis, Munro micro-abscess, elongation of rete pegs, granulosa thinning, and lymphocyte infiltration. We previously profiled gene expression and chromatin accessibility of psoriatic skins by transcriptome sequencing and ATAC-seq. However, integrating both of these datasets to unravel gene expression regulation is lacking. Here, we integrated transcriptome and ATAC-seq of the same psoriatic and normal skin tissues, trying to leverage the potential role of chromatin accessibility and their function in histopathology features. RESULTS: By inducing binding and expression target analysis (BETA) algorithms, we explored the target prediction of transcription factors binding in 15 psoriatic and 19 control skins. BETA identified 408 upregulated genes (rank product < 0.01) and 133 downregulated genes linked with chromatin accessibility. We noticed that cumulative fraction of genes in upregulation group was statistically higher than background, while that of genes in downregulation group was not significant. KEGG pathway analysis showed that the upregulated 408 genes were enriched in TNF, NOD, and IL-17 signaling pathways. In addition, the motif module in BETA suggested the 57 upregulated genes are targeted by transcription factor AP-1, indicating that increased chromatin accessibility facilitated the binding of AP-1 to the target regions and further induced expression of relevant genes. Among these genes, SQLE, STRN, EIF4, and MYO1B expression was increased in patients with hyperkeratosis, parakeratosis, and acanthosis thickening. CONCLUSIONS: In summary, with the advantage of BETA, we identified a series of genes that contribute to the disease pathogenesis, especially in modulating histopathology features, providing us with new clues in treating psoriasis.
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Paraceratose , Psoríase , Cromatina/genética , Metilação de DNA , Humanos , Paraceratose/genética , Psoríase/genética , Fator de Transcrição AP-1/genética , TranscriptomaRESUMO
Infantile pustular psoriasis (IPP) is an extremely rare skin disease associated with genetic factors. Gene mutations of IL36RN (interleukin-36 receptor antagonist), CARD14 (caspase recruitment family member 14), and AP1S1 (the σ1C subunit of the adaptor protein complex 1) had been identified to be involved in the pathogenesis of IPP. IPP usually develops with no preceding psoriasis vulgaris (PV) or familial history. Here, we report a case of a 6-month-old infant and make the diagnosis of IPP by a series of examinations; subsequently, by detecting coexistent mutations of IL36RN and CARD14, the diagnosis is intensified from a genetic point of view. We treated the child with traditional oral and topical drugs regardless of the commonly used acitretin considering its potential side effects, such as skeletal toxicity, and the lesions got conspicuous improvement with much reduction of inflammation. Owing to the genetic mutation of IL-36, there had been reported cases focusing on anti-IL36 biological agents in the treatment of IPP, and it could be a new weapon to treat and improve such IL-36RN-deficient skin diseases.
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Psoriasis is an immune-mediated genetic disease involving innate and the adaptive immune system. Aurora kinase A (AURKA) belongs to a seine/threonine kinases family and is elevated in lesional psoriatic tissues. This research aimed to investigate the effects of AURKA on psoriasis progression and whether it worked by regulating autophagy or inflammasome activation. The results showed that the expression of AURKA was higher in psoriasis tissue than that in the psoriasis skin. IFN-γ (100 ng/mL) plus poly (dA:dT) (2 mg/mL) induced the increased AURKA, secretion of IL-1ß, IL-18 and the active form of caspase-1 (p20). AURKA knockdown inhibited the inflammatory responses of keratinocytes and the activation of AIM2 inflammasome, and enhanced autophagy. 3MA (autophagy inhibitor) attenuated the effects of AURKA on AIM2 inflammasome. In addition, AURKA promoted the activation of the AKT/mTOR pathway. Akt inhibitor (PI-103) attenuated AIM2 inflammasome activation induced by Aurka overexpression. In conclusion, this research demonstrated that AURKA promoted the psoriasis-related inflammation by blocking autophagy-mediated AIM2 inflammasome suppression. AURKA has the potential to be explored as a new promising target for the treatment for psoriasis.
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Aurora Quinase A/imunologia , Autofagia/imunologia , Proteínas de Ligação a DNA/imunologia , Inflamassomos/imunologia , Psoríase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Psoríase/patologiaRESUMO
BACKGROUND: Vitiligo is a complex disease in which patchy depigmentation is the result of an autoimmune-induced loss of melanocytes in affected regions. On the basis of a genome-wide linkage analysis of vitiligo in the Chinese Han population, we previously showed significant evidence of a linkage between 22q12 and vitiligo. Our aim in the current study was to identify vitiligo susceptibility variants within an expanded region of the 22q12 locus. METHODS AND RESULTS: An in-depth analysis of the expanded region of the 22q12 locus was performed by imputation using a large GWAS dataset consisting of 1117 cases and 1701 controls. Eight nominal SNPs were selected and genotyped in an independent cohort of Chinese Han individuals (2069 patients and 1370 control individuals) by using the Sequenom MassArray iPLEX1 system. The data were analyzed with PLINK 1.07 software. The C allele of rs730669 located in ZDHHC8/RTN4R showed a strong association with vitiligo (P = 3.25 × 10-8, OR = 0.81). The C allele of rs4820338 located in VPREB1 and the A allele of rs2051582 (a SNP reported in our previous study) located in IL2RB showed a suggestive association with vitiligo (P = 1.04 × 10-5, OR = 0.86; P = 1.78 × 10-6, OR = 1.27). The three identified SNPs showed independent associations with vitiligo in a conditional logistic regression analysis (all P < 1.0 × 10-5; all D' < 0.05 and r2 < 1.0 × 10-4). CONCLUSIONS: The study reveals that two novel variants rs730669 (ZDHHC8/RTN4R) and rs4820338 (VPREB1) on 22q11.2 might confer susceptibility to vitiligo and affect disease subphenotypes. The presence of multiple independent variants emphasizes their important roles in the genetic pathogenesis of disease.
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Cromossomos Humanos Par 22/genética , Vitiligo/genética , Aciltransferases/genética , Adolescente , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Estudos de Coortes , Etnicidade/genética , Feminino , Frequência do Gene/genética , Ligação Genética/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Cadeias Leves Substitutas da Imunoglobulina/genética , Masculino , Proteínas de Membrana/genética , Receptor Nogo 1/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal activation of T cells and caused by an imbalance in the production and clearance of apoptotic cells. We previously showed that the transcription regulator Bach2 regulated abnormal B-cell activation in SLE. Here, we investigated whether Bach2 was also involved in Th9 cell differentiation in SLE. We found that the proportion of Th9 cells was enhanced in the peripheral blood mononuclear cells (PBMC) of SLE patients. The PBMC and CD4+ T cells of SLE patients exhibited a decrease of Bach2 expression and an increase of IL-9 expression. Furthermore, Bach2 overexpression significantly repressed the levels of PU.1, IRF4, IL-9, and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. In addition, Bach2 overexpression inhibited the levels of IL-9 and Th9 cells, whereas IRF4 upregulation enhanced the levels of IRF4 and IL-9 and Th9 cells in the CD4+ T cells of SLE patients and healthy volunteers. The effect of IRF4 up-regulation was abolished by Bach2 overexpression. In summary, our work suggests that Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in SLE, and thus, Bach2 may be a novel potential target for SLE treatment.
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Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Feminino , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Masculino , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Psoriasis is a chronic inflammatory skin disease which mainly involves immune system. This research was to investigate the role of MST1 in the psoriasis, and the detailed mechanism whether related with Th17 and NF-κB. The skin samples and peripheral blood were obtained from psoriasis patients. Skin samples and T cells isolated from peripheral blood of patients were cultured in vitro. The results showed that the level of MST1 in the lesional skin of all three patients was higher than that of un-lesional skin, as well as the amount of CD4, CD8 and IL17 positive T cells. The amount of circulating Th17 was higher than that of control. The level of MST1, IL-17, IL-22 and TNFα was enhanced in activated T cells (p < 0.01), which indicated that MST1 increased markedly in activated T cells. The proliferation and migration of T cells were decreasing in MST1 knockdown cells, while increasing in overexpressed cells, as well as the production of IL-17, IL-22 and TNFα. MST1 enhanced the activation of TLR4-NF-κB signaling pathway, and TLR4 knockdown could reverse the effect of MST1 on NF-κB activation. This research indicated that MST1 could regulate the activation of Th17 in psoriasis partly through TLR4-NF-κB pathway. MST1 may be a target for treatment of psoriasis.
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Ativação Linfocitária/genética , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Psoríase/genética , Psoríase/imunologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Células Th17/imunologia , Receptor 4 Toll-Like/metabolismo , Adulto , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Ativação Linfocitária/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Forty-nine susceptible loci have been reported to be significantly associated with vitiligo by genome-wide association studies (GWASs) in European-derived whites. To date, some of these reported susceptibility loci have not yet been validated in the Chinese Han population. The purpose of this study was to examine whether the 16 reported susceptible loci in European-derived whites were associated with vitiligo in the Chinese Han population. Imputation was performed using our previous GWAS dataset by IMPUTE v2.2.2. The 16 imputed top single-nucleotide polymorphisms (SNPs) with suggestive signals, together with the reported SNPs, were genotyped in a total of 2581 patients and 2579 controls by the Sequenom MassARRAY system. PLINK 2.0 software was used to perform association analysis. The dbSNP database, HaploReg, and eQTL data were adopted to annotate the biological function of the SNPs. Finally, four SNPs from three loci were significantly associated with vitiligo, including rs3747517 (P = 1.29 × 10-3, OR = 0.87) in 2q24.2, rs4807000 (P = 7.78 × 10-24, OR = 0.66) and rs6510827 (P = 3.65 × 10-5, OR = 1.19) in 19p13.3, and rs4822024 (P = 6.37 × 10-10, OR = 0.67) in 22q13.2. According to the dbSNP database, rs3747517 is a missense variant of IFIH1, rs4807000 and rs6510827 are located in TICAM1, and rs4822024 is located 6 kb upstream of TEF. Further bioinformatics analysis by HaploReg and eQTL found that rs4807000, rs6510827, and rs4822024 are involved in regulating gene expression. Our study revealed the strong association of 2q24.2 (rs3747517), 19p13.3 (rs4807000, rs6510827), and 22q13.2 (rs4822024) with the risk of vitiligo in the Chinese Han population, which implicates common factors for vitiligo across different ethnicities, and helps expand the understanding of the genetic basis of this disease.
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Objective: The purpose of this study was to investigate associations between the 14 reported loci (from a meta-analysis of genome-wide association studies [GWAS] in the Caucasian population) and vitiligo in the Chinese Han population. Materials and Methods: In this study 14 single nucleotide polymorphisms (SNPs) at 14 different genetic loci were evaluated for their association with viteligo in a Chinese Han cohort, including 1472 cases and 1472 controls of by using the Sequenom MassArray iPLEX1 system. A Bonferroni adjustment was used for multiple comparisons and pBonferroni <0.0056 was considered statistically significant. Results: The T allele of the locus within the FBXO45-NRROS gene (3q29) was significantly associated with vitiligo (odds ratio = 1.22, 95% confidence interval: 1.10-1.36, p = 0.0001). Association at the genotype level was strong (p = 0.0007). The other SNPs were not associated with vitiligo (pBonferroni >0.0056). Conclusion: A SNP at the rs6583331 locus 3q29 is associated with the susceptibility of vitiligo in the Chinese Han population, which suggests that there is a common genetic factor predisposing to the development of vitiligo in the Chinese and Caucasian populations.
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Proteínas F-Box/genética , Proteínas de Ligação a TGF-beta Latente/genética , Vitiligo/genética , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Etnicidade/genética , Proteínas F-Box/metabolismo , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Proteínas de Ligação a TGF-beta Latente/metabolismo , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Lysine 2-hydroxyisobutyrylation is a newly discovered posttranslational modification. Although this modification is an important type of protein acylation, its role in psoriasis remains unstudied. We compared lesional and nonlesional psoriasis skin samples from 45 psoriasis patients. The result showed that this highly conserved modification was found in large quantities in both normal and diseased dermal tissues. However, there were a number of clear and significant differences between normal and diseased skin tissue. By comparing, lysine 2-hydroxyisobutyrylation was upregulated at 94 sites in 72 proteins and downregulated at 51 sites in 44 proteins in lesional skin. In particular, the sites with the most significant downregulation of lysine 2-hydroxyisobutyrylation were found in S100A9 (ratioâ¯=â¯0.140, p-valueâ¯=â¯.000371), while the most upregulated site was found in tenascin (ratioâ¯=â¯3.082, p-valueâ¯=â¯.0307). Loci associated with psoriasis, including FUBP1, SERPINB2 and S100A9, also exhibited significant regulation. Analyses of proteome data revealed that SERPINB2 and S100A9 were differentially expressed proteins. And bioinformatics analysis suggest that the P13K-Akt signaling pathway was more enriched with lysine 2-hydroxyisobutyrylation in lesional psoriasis skin. Our study revealed that lysine 2-hydroxyisobutyrylation is broadly present in psoriasis skin, suggesting that this modification plays a role in psoriasis pathogenesis. SIGNIFICANCE: A newly discovered protein posttranslational modification, lysine 2-hydroxyisobutyrylation, has been found to occur in a wide variety of organisms and to participate in some important metabolic processes. In this study, lysine 2-hydroxyisobutyrylation in lesional psoriasis skin and nonlesional psoriasis skin was quantified and compared for the first time. We found a number of differentially modified proteins and sites in our comparisons. Interestingly, some of the identified proteins and pathways with significantly different modifications, such as S100A9 and the PI3K-Akt signaling pathway, have been previously reported to be associated with psoriasis. We hope that this research will provide new insights into psoriasis.
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Isobutiratos/metabolismo , Lisina/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Psoríase/metabolismo , Pele/metabolismo , Sequência de Aminoácidos , Biópsia , Estudos de Casos e Controles , Humanos , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Psoríase/patologia , Pele/patologiaRESUMO
The skin microbiota is an inseparable component of the skin barrier structure, which participates in the stabilization or impairment of the barrier function as well as the development of many skin diseases. To characterize the normal skin microbiota and its association with skin sites, age and sex, we recruited 50 volunteers divided into children, adolescents, young adults, middle-aged adults and the elderly. The skin sites consisted of cheeks, volar forearms (representing dry environments) and upper back (representing sebaceous environments). A total of 9 574 365 high-quality sequences of the V3 to V4 region of the 16S rRNA gene were annotated with taxonomic information related to two archaeal phyla (Thaumarchaeota and Euryarchaeota) and five dominant bacterial phyla (Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes and Cyanobacteria). The skin bacteria community structure was influenced by skin sites, and was closely related to age and sex. The upper back was dominated by Propionibacterium and Staphylococcus, and the cheeks facilitated the survival of Betaproteobacteria, while Alphaproteobacteria were prevalent on the volar forearms. Regarding the effects of age, after sexual maturity, the cheek microbiota became more similar to sebaceous sites (i.e. the upper back). The volar forearms appeared to experience the aging process earlier than the other two sites. The elderly had greater species richness and diversity and their community composition no longer had skin-site selectivity. Males had a greater species richness than females, but the sex differences in the community structure only present at certain age groups and skin sites.
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Bactérias/isolamento & purificação , Microbiota/genética , Pele/microbiologia , Adolescente , Adulto , Fatores Etários , Idoso , Bactérias/genética , Criança , Pré-Escolar , DNA Bacteriano , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/isolamento & purificação , Análise de Sequência de DNA , Fatores Sexuais , Adulto JovemRESUMO
To identify possible additional genetic susceptibility loci for pemphigus vulgaris (PV), we performed a genome-wide association study of 240 PV patients and 1,031 control individuals, and we selected the top single nucleotide polymorphisms for replication in independent samples, with 252 patient samples and 1,852 control samples. We identified rs11218708 (P = 3.1 × 10-8, odds ratio = 1.54) at chromosome locus 11q24.1 as significantly associated with PV. A fine-mapping analysis of PV risk in the major histocompatibility complex region showed three independent variants predisposed to PV using stepwise analysis: HLA-DRB1*14:04 (P = 2.47 × 10-38, odds ratio = 6.28), rs7454108 at the TAP2 gene (P = 2.78 × 10-12, odds ratio = 3.25), and rs1051336 at the HLA-DRA gene (P = 3.06 × 10-6, odds ratio = 0.33). A systematic evaluation using gene- and pathway-based analyses showed a high tendency for PV susceptibility genes to be associated with autoimmunity. Our study highlights the involvement of immune-mediated processes in the pathophysiology of PV and illustrates the value of imputation to identify variants in the major histocompatibility complex region.
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Genótipo , Complexo Principal de Histocompatibilidade/genética , Pênfigo/genética , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Autoimunidade/genética , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cadeias alfa de HLA-DR/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , RiscoRESUMO
This study was aimed to investigate whether NFKB1 participates in the pathogenesis of psoriasis by mediating Th1/Th17 cells. In this study, expression of NFKB1 was assessed in skin tissues from psoriasis patients and the healthy controls through Western blot and Immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum levels of IFN-γ, IL-17 (IL-17A) and IL-17RA. The imiquimod-induced psoriasis mouse model was employed to examine the role of NFKB1 in psoriasis via the assessment of psoriasis area and severity index (PASI), including erythema, thickness and scales. The effects of NFKB1 on Th1/Th17 cells in were examined by flow cytometry. In vitro co-culture of Th1/Th17 cells isolated from different mice with HaCat cells was conducted to elucidate the effect of Th1/Th17 cells-mediated by NFKB1 on HaCat cells by MTT, wound healing and transwell invasion assay, respectively. The results showed that NF-κB p105/p50 expression in skin tissues was significantly increased in psoriasis (nâ¯=â¯21) compared to the healthy controls (nâ¯=â¯16), as well as levels of serum INF-γ and IL-17. Additionally, NF-κB p105/p50 expression in lesional skin tissues was much higher than that in non-lesional skin tissues of the same patients. In the psoriasis mouse model, NFKB1 overexpression significantly elevated the scores of erythema, thickness and scales. Besides, NFKB1 up-regulated the level of NF-κB p105/p50, INF-γ, T-bet, IL-17 and RORγt, as well as Th1/Th17 cells in skin tissues of psoriasis mice. Finally, in vitro assay confirmed that the activation of Th1 and Th17 mediated by NFKB1 in psoriasis promoted the proliferation, migration and invasion of keratinocytes. These findings suggest a critical role for NFKB1 in the regulation of Th1 and Th17 in psoriasis.
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Interleucina-17/imunologia , Subunidade p50 de NF-kappa B/imunologia , Psoríase/imunologia , Células Th1/imunologia , Adulto , Animais , Linhagem Celular , Células Cultivadas , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Imiquimode , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Psoríase/induzido quimicamente , Psoríase/metabolismo , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Th1/metabolismo , Adulto JovemRESUMO
OBJECTIVE: This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. METHODS: Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR-ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. RESULTS: Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. CONCLUSIONS: Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway.
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Linfócitos B/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cromonas/farmacologia , Humanos , Imunoglobulina G/metabolismo , Morfolinas/farmacologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Vitiligo is an immune-related disease with patchy depigmentation of skin and hair caused by selective destruction of melanocytes. In recent decades, many studies have shown the association between vitiligo and HLA genes; however, the results of Han Chinese are scarce. In this study, we performed a fine-mapping analysis of the MHC region in 2818 Han Chinese subjects through a widely used HLA imputation method with a newly built large-scale Han-MHC reference panel. Three new four-digit HLA alleles (HLA-DQB1â¯∗â¯02:02, HLA-DQA1â¯∗â¯02:01 and HLA-DPB1â¯∗â¯17:01) were identified to be associated with the risk of vitiligo, and four previously reported alleles were confirmed. Further conditional analysis revealed that two important variants, HLA-DQß1 amino acid position 135 (ORâ¯=â¯1.79, Pâ¯=â¯1.87â¯×â¯10-11) and HLA-B amino acid positions 45-46 (ORâ¯=â¯1.44, Pâ¯=â¯5.61â¯×â¯10-11), conferred most of the MHC associations. Three-dimension ribbon models showed that the former is located within the ß2 domain of the HLA-DQß1 molecule, and the latter lies in the α1 domain of the HLA-B molecule, while both are involved in specific antigen presenting process. Finally, we summarized all significant signals in the MHC region to clarify their complex relationships, and 8.60% of phenotypic variance could be explained based on all reported variants in Han Chinese so far. Our findings highlight the complex genetic architecture of the MHC region for vitiligo in Han Chinese population and expand our understanding of the roles of HLA coding variants in the etiology of vitiligo.
Assuntos
Predisposição Genética para Doença/genética , Antígenos HLA/genética , Polimorfismo de Nucleotídeo Único , Vitiligo/genética , Alelos , Povo Asiático/genética , China , Mapeamento Cromossômico/métodos , Frequência do Gene , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Fatores de Risco , Vitiligo/etnologiaRESUMO
BACKGROUND: Vitiligo is an autoimmune disease, characterized by progressive loss of skin pigmentation, which is caused by the interactions of multiple factors, such as heredity, immunity and environment. Recently, a single nucleotide polymorphism (SNP) rs638893 at 11q23.3 region was identified as a risk factor for vitiligo in genome-wide association studies and multiple SNPs in this region have been associated with other autoimmune diseases. OBJECTIVE: This study aims to identify additional susceptibility variants associated with vitiligo at 11q23.3 in the Chinese Han population. METHODS: We selected and genotyped 26 SNPs at 11q23.3 in an independent cohort including 2924 cases and 4048 controls using the Sequenom MassArray iPLEX® system. Bonferroni adjustment was used for multiple comparisons and P value <1.92×10-3 (0.05/26) was considered statistically significant. RESULTS: The A allele of rs613791 and G allele of rs523604 located in CXCR5 were observed to be significantly associated with vitiligo (OR=1.21, 95% CI: 1.11-1.31, P=1.20×10-5; OR=1.14, 95% CI: 1.07-1.23, P=1.90×10-4, respectively). The C allele of rs638893 (a previously reported one) located upstream of DDX6 was also significantly associated with vitiligo (OR=1.25, 95% CI: 1.12-1.38, P=3.04×10-5). The genotypes distribution of 3 SNPs also showed significant differences between case and control (rs613791: P=7.00×10-6, rs523604: P=4.00×10-3, rs638893: P=1.20×10-5, respectively). The two newly identified SNPs (rs613791 and rs523604) showed independent associations with vitiligo by linkage disequilibrium analysis and conditional logistic regression. CONCLUSIONS: The study identified two new independent signals in the associated locus 11q23.3 for vitiligo. The presence of multiple independent variants emphasizes an important role of this region in disease susceptibility.
Assuntos
Povo Asiático/genética , Doenças Autoimunes/genética , Cromossomos Humanos Par 11/genética , Predisposição Genética para Doença , Receptores CXCR5/genética , Vitiligo/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Técnicas de Genotipagem/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08×10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66×10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75×10-3) and rs1837253 (P = 5.30×10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD.